The objectives of this research project are to design and develop safe and efficient multifunctional delivery systems for systemic and target-specific delivery of small interfering RNA (siRNA) to treat human diseases with RNA interference (RNAi). RNAi is a natural mechanism for gene silencing and has a great potential to treat human disease by turning off specific disease related genes. Recent preclinical and clinical studies have demonstrated that gene silencing with siRNA can be effective to treat a spectrum of human diseases, including cancer, viral infections, ocular diseases, autoimmune diseases and neurological disorders. However, clinical development and use of siRNA are limited by the lack of safe and efficient in vivo delivery systems. We have recently developed a novel class of multifunctional delivery systems with the functionalities of nanoparticle formation with siRNA, pH-sensitive amphiphilicity, amphiphilic cell membrane disruption specifically at the endosomal-lysosomal pH, environment-responsive siRNA release and specific targeting, for efficient systemic and specific in vivo siRNA delivery. The specific aims of this project are to design, synthesize and characterize optimized multifunctional carriers for systemic in vivo delivery of small interfering RNA and to evaluate in vitro biological properties of the multifunctional carriers and peptide targeted siRNA delivery systems, including cytotoxicity, pH-sensitive cell membrane disruption, cell uptake, endosomal-lysosomal escape, siRNA delivery efficiency, and in vivo delivery efficiency of a lead targeted delivery system with a model therapeutic siRNA, anti-HIF-1a siRNA, and their efficacy of anti-cancer treatment in animal tumor models. The novel multifunctional siRNA delivery system will have better safety profiles and higher specificity and efficiency for in vivo siRNA delivery than currently available siRNA delivery systems. The long-term goal of this project is to develop safe, efficient and specific delivery systems of siRNA for the treatment of human diseases. PUBLIC HEALTH RELEVANCE: Turning off disease related genes is promising to treat a spectrum of human diseases that cannot be efficaciously treated with currently available treatment methods. Novel delivery systems with better safety profiles and high delivery efficiency will facilitate the clinical development and application of this new treatment by specific delivery of the effectors for gene regulation into their targets.